It is known that pain is pharmacologically treated by using non-steroidal anti-inflammatory drugs (NSAID), such as salicylates which mechanism of action is located in the peripheral sites, and the hypnotic-analgesics which action is focused in the central nervous system. The NSAIDs are a group of compounds widely used and well tolerate due to low incidence of severe side effects. The NSAID are very effective for regulating peripheral somatic pain, especially related to inflammatory processes. Due to the mechanism of action based on inhibition of ciclooxigenase enzymes type 1 (Nature New Biology, 2001, 231:232-235) and type 2 (PNAS, 1991, 88:2692-2696) the efficacy of NSAIDs for treatment of pains such as colic caused by obstruction, trauma, nerve compression or central nervous system pain, is limited. Few drugs are available for treatment of this modality of pain.
The pharmacological group recommended for the control of high intensity pain is the opioid, which the prototype compound is morphine, and even in this group few drugs are available. Clinical use of morphine and related drugs is not dissociated of several side effects as nausea, vomiting, itching and respiratory depression, which frequently interrupts the treatment. More recently, a therapeutic protocol to increase the potency of a drug based on association of an adjuvant compound with a main compound has been developed for treatment of patients with sustained pain. Thus, the adjuvant compound is directed to increase the efficacy and also the duration of the effect of drug like morphine for pain treatment. The main advantage of simultaneously use an adjuvant compound is the reduction of dose and frequency of administration of the main active drug, thus reducing side effects.
Besides the possibility to increase the analgesic effect of a drug such as morphine, an adjuvant compound also potentiates the intensity and duration of anesthesia induced by intrathecal administration of local anesthetics. This procedure is frequently recommended for abdominal lower surgery and for patients with chronic pain. One group of compounds that has been used for this purpose is the alpha-2 adrenoceptor agonists, such as clonidine. The efficacy of alpha-2 adrenoceptor agonists as analgesic is lower than the morphine, however, the ability for increasing the intensity and duration of analgesia of this drug in combination with other drugs is significant (Anesthesiology 1994, 80:837).
Other relevant pharmacological properties of alpha-2 adrenoceptor agonists are sedative and hypnotic effects (Anesthesiology 1988, 69:818-823). Although the efficacy as a hypnotic by itself is not as high as the barbiturates, alpha-2 adrenoceptor agonists are useful as pre-anesthetics drugs agent and as adjuvants for intravenous (Br. J. Anaesth. 1990, 65:157-163) and inhalation general anesthetics (Anesthesiology 1987, 67:11-19).
Hypotension is the main side effect related to the administration of alpha-2 adrenoceptor agonists due to their action in the important area of the brain that regulates the sympathetic nervous system outflow (Naunyn Schmiedebergs Arch Pharmacol., 1981, 317:120-125). This pharmacological effect for alpha-2 adrenoceptor agonists is known for several years even before the description of analgesic and sedative effect. For this reason, clonidine is classified as a hypertensive drug for therapy in classical pharmacological textbooks.
Due to the fact that alpha-2 adrenoceptors agonists used as adjuvants of analgesic and hypnotic compounds may cause decreasing of blood pressure, it is important to find new drugs with properties similar to clonidine but hemodynamically more stable.
Finding new prototype with central nervous system analgesic effect and adjuvant for anesthesia is clinically relevant due to limited number of drugs with these properties. Clonidine was one of the few drugs available (U.S. Pat. No. 4,094,964), and, more recently the isomer of medetomidine, dexmedetomidine, is also available (U.S. Pat. No. 5,091,402) both with alpha-2 adrenoceptor agonist activity.